The present invention relates to a transdermal therapeutic system for the controlled release of estradiol or its pharmaceutically acceptable derivatives alone or combined with gestagens, such as levonorgestrel, to human or animal skin. The present invention further relates to the use and to a process for the production of this system.
In the therapy of various diseases, transdermal therapeutic systems (TTS) have been introduced on the market. Also, transdermal therapeutic systems containing the estrogenic active substance 17-.beta.-estradiol used as therapeutic agent for climacteric complaints and--for some time now--against osteoporosis are commercially available and show good therapeutic results.
Levonorgestrel is a synthetic gestagen derivative which has mainly been used in contraceptives in combination with orally effective estrogens. In such preparations gestagens, consequently including levonorgestrel, have the function to cause a "physiologic" abstraction hemorrhage which is as short and rapid as possible by means of an adequate trophic premedication of the uterus. There are also hints that the gestagen addition has a protective effect against the risk of endometrial tumors.
For this reason, it is appropriate to use a cyclic treatment also for the indication of postmenopausal complaints, i.e., to make use of a temporary fixed drug combination consisting of estrogens (e.g., estradiol) and gestagens (e.g., levonorgestrel). A combination of the two active substances in a common, monolithic transdermal therapeutic system which would have to be applied only once a day or even once to twice a week is particularly interesting. Owing to its high efficiency and permeativity through the skin levonorgestrel is excellently suitable for such a system.
Experimental systems for the transdermal delivery of levonorgestrel are described in literature (Friend et. al., J. Controlled Release 7, 243-250 (1988)). However, according to this estimation, permeation improvers (enhancers), e.g., alkyl esters of short-chain fatty acids, are required for the successful transdermal therapy with sufficiently small system surfaces (Friend et. al., J. Controlled Release 9, p. 33-40 (1989)).
Numerous devices for the transdermal application of estrogens and gestagens have been disclosed. Nakagawa et al. (EP-A 0 483 370) obtained a matrix-type transdermal therapeutic system for estradiol alone by using styrene-isoprene block copolymer, moisture-absorbing polymer domains, and the enhancer (and antipruritic agent) crotamiton. Another conception is the simultaneous application of estradiol and an enhancer (ethanol) in a membrane-controlled reservoir system (Campbell et al., U.S. Pat. No. 4,379,454); this can also be used in a combined administration form comprising the gestagen norethisterone acetate (Frankhauser and Schenkel, DE 3 810 896).
However, transdermal therapeutic systems for the release of estradiol and/or gestagens have the disadvantage that they either contain ethanol or that they exhibit the potential danger of the active substance being recrystallized in the course of time.
It is known from DE-OS 32 05 258 and EP 0 285 563 to administer estradiol and ethanol simultaneously in a patch formulation. However, the production of this patch is very expensive, and the wearing comfort after application is low because of missing flexibility.
EP 0 285 563 describes a transdermal therapeutic system for the combined application of estrogens and gestagens. The reservoir has the active substance formulation, optionally a membrane, and ethanol as percutaneous absorption improving agent. Since the release of the active substance is mainly controlled by the membrane, this transdermal therapeutic system is completely different from the active-substance-containing patch according to the present invention. In the patch described in said publication, the adhesive has the mere function of fastening the patch to the skin. The fact that it can contribute to the control of the active substance release is not its main function but merely a--probably even undesired--side effect. It is a so-called "pouch patch" since the active substance preparation is present in a pouch consisting of an impermeable backing layer and a membrane having an adhesive layer. As a consequence of its complicated structure, the production of this patch is very expensive since the individual components have to be produced separately and then joined in an additional step to form a patch.
EP 0 275 716 describes a two-layer transdermal therapeutic system--in contrast to the single-layer system according to the present invention--for the simultaneous administration of one or several estrogens which are dissolved or microdispersed in the polymeric layer. In addition to the active substances, the pressure sensitive adhesive layer comprises substances improving the transdermal absorption. Polymeric and pressure sensitive adhesive layer may consist of polyacrylates, silicones, or polyisobutylenes.
EP 0 072 251 describes a flexible, liquid-absorbing medicinal bandage. The substrate which is attached to the flexible backing layer consists of a hydrophilic matrix based on hydrophilic high-molecular polysaccharides and/or polyacrylic acid, polyacrylamide, ethylene-vinyl acetate-copolymers, and other polymers as well as of a liquid phase based on a solution or emulsion of carbohydrate, proteins, multivalent alcohols, and different active substances, amongst others hormones. The main feature of this invention is the moisture-absorbing adhesive.
EP 0 328 806 describes a transdermal therapeutic system without membrane; its matrix consists of a polyacrylate adhesive, a solvent, a penetration enhancer, and estrogens, the derivatives and combinations thereof.
WO 87/07 138 describes an estradiol patch based on a backing layer, an active-substance-containing matrix and a pressure sensitive adhesive covered with a removable protective layer. The matrix and pressure sensitive adhesive are manufactured in technologically very expensive operations by homogenizing, degassing, coating, drying, and separating. According to an embodiment, the backing layer has to be coated with a pressure sensitive adhesive, resulting in an additional operation. The individual parts are joined in a separate step. For this reason, the production of this patch is very expensive and complicated.
U.S. Pat. No. 4,624,665 describes systems comprising the active substance in microencapsulated form within the reservoir. The reservoir is embedded between the backing layer and a membrane. The outer edge of the system is provided with a pressure sensitive adhesive. The structure and the production of this system are very complicated since the active substance has to be microencapsulated and homogeneously distributed in a liquid phase which is then embedded between backing layer and membrane in additional process steps. In addition, this system must then be provided with an adhesive edge and covered with a protective layer.
Additionally, EP 0 186 019 describes active substance patches wherein water-swellable polymers are added to a rubber/adhesive-resin-mass and from which estradiol can be released. However, it turned out that the release of estradiol from these active substance patches is too low and does not meet the therapeutic requirements.
DE-OS 20 06 969 describes a patch or pressure sensitive adhesive dressing exhibiting system action; it contains contraceptive substances which are incorporated in the adhesive component or in the adhesive film. This publication discloses that the adhesive may be an acrylate.
DE-OS 39 33 460 describes an estrogen-containing active substance patch based on homo and/or copolymers with at least one derivative of the acrylic acid or with methacrylic acid in combination with water-swellable substances.
However, it turned out that pressure sensitive adhesive transdermal therapeutic matrix systems which comprise the active substance in a partially or completely dissolved form involve the potential risk that the active substance recrystallizes in the course of time. Thus the active substance release decreases and the estrogen-containing patch does no longer meet the therapeutic requirements.
Another drawback of systems according to the state of the art is the use of enhancers, this results in a fundamentally undesired additional skin affection including the risk of irritation. Additional disadvantages lie in the expensive construction of these systems (use of several active-substance-containing layers, use of controlling membranes), generally rendering the finished product unacceptable for the user.